PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer

Abstract

PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA-mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G 0 /G 1 phase arrest regardless of PIK3CA mutational status. The alpelisib and paclitaxel combination demonstrated synergistic anti-proliferative effects, preferentially on PIK3CA-mutant cells, resulting in increased DNA damage response and apoptosis. In addition, alpelisib and paclitaxel combination potentiated anti-migratory activity in PIK3CA-mutant cells. Alpelisib partially reversed epithelial-mesenchymal transition markers in PIK3CA-mutant cells. In a xenograft model of MKN1 cells, the alpelisib and paclitaxel combination significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing apoptosis. Moreover, this combination tended to prolong the survival of tumor-bearing mice. Our data suggest promising anti-tumor efficacy of alpelisib alone or in combination with paclitaxel in PIK3CA-mutant GC cells. Gastric cancer (GC) is the fifth most common cancer and the third leading cause of death worldwide 1. In South Korea, GC is the second most common cancer and its incidence is significantly higher than that in Western countries 2. A substantial proportion of patients with GC is diagnosed at the advanced or metastatic stage and has a poor prognosis. Recent development of targeted agents has significantly improved the clinical outcome of patients with various advanced solid tumors, especially breast cancer, lung cancer, and some hematological malignancies. In the meantime, numerous clinical trials have been conducted on GC. However, most trials were not successful except those utilizing trastuzumab, ramucirumab, and nivolumab 3-5. Therefore, there is huge and urgent need to develop novel therapeutic strategies for the management of patients with advanced or metastatic GC, based on specific targets in the cancer cells. The Cancer Genome Atlas Research Network previously identified that PIK3CA is the third most frequently mutated gene, following TP53 and ARID1A in GC 6. PIK3CA mutations are present in approximately 9-13% of patients with non-hypermutated GC and 32% of patients with hypermutated GC. Phosphatidylinositol 3-kinase (PI3K) signaling pathway is important in cancer cell proliferation and survival 7. PI3K contains regulatory p85 and catalytic p110 subunits. PIK3CA encodes p110α, which is a PI3K catalytic subunit. Mutant PIK3CA is known to promote the proliferation and invasion of human cancer cells 8. We reported that PIK3CA mutations are associated with increased tumor aggressiveness and AKT activation in patients

Paclitaxel treatment enhances lymphatic metastasis of B16F10 melanoma cells via CCL21/CCR7 axis

“…Paradoxical effects of chemotherapy on tumour relapse and metastasis promotion were recognised in recent years 31 . PTX, a drug that induces mitotic arrest due to activation of the mitotic checkpoint, can promote tumour metastasis 13 , 32 . Specifically, PTX-induced tumour metastasis is a complex process involving several molecular mechanisms 31 .…”

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

“…The PI3K/AKT and Wnt/β-catenin pathways also play a role in synergistic lethality in cancer therapy. In gastric cancer, synergistic lethality for combination therapy with paclitaxel and PI3K p110α-specific inhibitor alpelisib was found to be stronger in PIK3CA-mutant cells related to enhanced DDR and apoptosis, as demonstrated by γ-H2ax and caspase 3/7 assays, respectively ( 149 ). Indeed, Juvekar et al have demonstrated that PI3K3CA inhibition of breast cancer cells by alpelisib can produce raised nucleotide depletion-mediated DNA damage and thus death of cancer cells ( 150 ).…”

In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors

“…The combination of alpelisib with paclitaxel is currently being studied in breast cancer patients and advanced solid tumors [39,40]. In gastric cancer, alpelisib and paclitaxel demonstrated synergistic anti-proliferative and anti-migratory effects in PIK3CA mutant cells [41]. In a xenograft model utilizing gastric cancer cells, alpelisib and paclitaxel significantly increased apoptosis and tended to prolong the survival of tumor-bearing mice.…”